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  • Title: VCAM-1-binding peptide targeted cationic liposomes containing NLRP3 siRNA to modulate LDL transcytosis as a novel therapy for experimental atherosclerosis.
    Author: Jia X, Bai X, Yang X, Wang L, Lu Y, Zhu L, Zhao Y, Cheng W, Shu M, Mei Q, Jin S.
    Journal: Metabolism; 2022 Oct; 135():155274. PubMed ID: 35917895.
    Abstract:
    BACKGROUND: Activation of NLRP3 inflammasome accelerates the formation of atherosclerotic plaques. Here, we evaluated the effects of inflammation on the expression of the NLRP3 inflammasome in endothelial cells (ECs). METHODS: The effect of TNF-α on transcytosis of LDL was measured. VCAM-1 binding peptide targeting cationic liposomes (PCLs) were prepared as siRNA vectors. Methylated NLRP3 siRNA was encapsulated into the PCLs to knock down NLRP3 in vitro and in vivo. In rats with partial carotid ligation, TNF-α-induced LDL retention in the carotid artery endothelium was observed. In ApoE-/- mice, NLRP3 siRNA-PCLs were injected intravenously to observe their effect on the formation of atherosclerosis. RESULTS: Our results showed that TNF-α upregulated NLRP3 in ECs, promoting the assembly of the NLRP3 inflammasome and processing of pro-IL-1β into IL-1β. Moreover, TNF-α accelerated LDL transcytosis in ECs. Knockdown of NLRP3 prevented TNF-α-induced NLPR3 inflammasome/IL-1β signaling and LDL transcytosis. Using optimized cationic liposomes to encapsulate methylated NLRP3 siRNA, resulting in targeting of VCAM-1-expressing ECs, to knockdown NLRP3, TNF-α-induced NLRP3 inflammasome activation and LDL transcytosis were prevented. Using the partial carotid ligation as an atherosclerosis rat model, we found that local administration of NLRP3 siRNA-PCLs efficiently knocked down NLPR3 expression in the carotid endothelium and dramatically attenuated the deposition of atherogenic LDL in carotid ECs in TNF-α-challenged rats. Furthermore, NLRP3 siRNA-PCLs were injected intravenously in ApoE-/- mice, resulting in reduced plaque formation. CONCLUSION: These findings established a novel strategy for targeting the NLRP3 inflammasome using NLRP3 siRNA-PCLs to interrupt LDL transcytosis, representing a potential novel therapy for atherosclerosis.
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